Microbiome: The “Hidden Organ” That Plays a Complex Role in Cancer, Part II

Part II: Practical Implications of Evolving Knowledge
October 10, 2017
Lada Krilov, PhD, ASCO Staff

ASCO Perspective
“As with most areas of life, ‘diversity’ is highly valued. Microbiome diversity promotes a potent immune defense against cancer and may impact the effectiveness of our cancer-directed immunotherapies. These immunotherapies are revolutionizing cancer care across diseases. Further rigorous scientific studies of the relationship of the microbiome and the immune system will be critical to better prevention and treatment of cancer in the coming decades.”

  • Steven J. O’Day, MD, ASCO Expert ​

Can the Microbiome Shield Us from Cancer? 

While there is inconclusive evidence as to which microbial species are most important for health, it seems clear that the more diverse the microbial composition, the better. A diverse microbiome can protect us from cancer by:

  • outcompeting (displacing) cancer-causing pathogens
  • reducing inflammation
  • priming immune responses

Meanwhile, there is growing evidence for the microbiome’s role in bolstering immune defenses against cancer. Immune responses to gut bacteria seem to help stimulate immune responses to cancer. In addition, through molecular cues, such as cytokine IL-10, beneficial gut bacteria can dial down inflammation and strengthen anticancer T-cell responses not only in the gut but throughout the body.7

Certain gut bacteria produce a molecule called butyrate that stimulates key players in cancer control – regulatory T cells and helper T cells. Butyrate also exerts a direct effect on cancer cells, by turning off genes involved in cell growth and turning on genes that trigger cell suicide (apoptosis).1 Early research showed that butyrate can block the growth of colon cancer cells in vitro, and experiments in mice suggest that dietary intake of probiotics and/or prebiotics with soluble fiber may increase butyrate production and slow tumor development.

Besides fiber, gut bacteria can use other dietary sources to produce a range of cancer-preventive chemicals:

  • anti-inflammatory urolithins are produced from ellagic acid (found in berries, walnuts, pomegranates)
  • antioxidant equol is produced from daizdein (found in soy-based foods)
  • anti-inflammatory and cancer-blocking  isothiocyanites are produced from glucosinolates (found in cruciferous vegetables like broccoli and cabbage)
  • anti-inflammatory conjugated linoleic acid is produced from linoleic acid (a component of vegetable oils)

A fiber-rich diet can increase the abundance of cancer-preventive, butyrate-producing bacteria in the gut. High-protein, low-carbohydrate diets on the other hand may change fermentation in the intestine, leading to increased levels of harmful nitrosamines, and decreased levels of protective molecules like butyrate and phenols.2 Other research suggests that a high-fat diet can change the microbiome in a way that increases bacterial production of the bile acid DCA, which promotes colon and esophageal cancers. Although there is still controversy on this topic, collectively these findings suggest that consuming a plant-based, fiber-rich diet may help reduce cancer risk.

Interestingly, epidemiologic studies have found that the rates of certain cancers are higher among people who had fewer bacterial infections as children. According to the so-called “cancer hygiene hypothesis,” the high popularity of hand sanitizers, antibacterial soaps and processed food can result in under-exposure to microbes, including those that protect us from cancer.8  Ultra cleanliness has also been linked to rising rates of allergies and autoimmune diseases.

How Microbes Extend the Legs of Cancer Therapy

Research reported over the past decade suggests that the ability of cancer therapies to control cancer long-term depends on activation of the immune system. The microbiome appears to play a key role in awakening immune defenses against cancer during cancer therapy.

Studies in mice show that chemotherapy is much more efficient in normal mice than in germ-free mice (or mice treated with powerful antibiotics to wipe out the gut microbiome).3 According to other mouse studies and some early human studies, the gut microbiome also helps enhance the efficacy of immunotherapy. Scientists have recently discovered that particular species of gut bacteria increase the therapeutic benefit from CTLA-4 blockade (Bacteroides) in melanoma, while others enhance the effect PD-1 blockade (Clostridiales) and PD-L1 blockade (Bifidobacterium).8,9-11 These insights suggest that individual differences in microbiome composition may be one of the reasons these immunotherapies work better in some people than others.11,12 

Scientists have a theory to explain the beneficial effects of gut bacteria during cancer treatment.3 Chemotherapy (cyclophosphamide and platinum salts) and immunotherapy can damage the intestinal lining, allowing certain types of gut bacteria and bacterial byproducts to leak into the blood circulation. Once they reach lymph nodes and lymphoid organs, these bacteria prime Th1 and Th17 T cells, which help recruit other immune cells to the tumor.

Microbiome Remodeling – A Possible New Strategy Against Cancer

Microbiome research is a young, but fast-growing field. It is clear from animal and early clinical studies that the effect of the microbiome on cancer should not be discounted. While there are still many open questions, in the not so distant future, cancer care will likely include an analysis of the patient’s microbiome at diagnosis to inform personalized treatment planning. It may also be possible to manipulate the microbiome to optimize treatment outcomes.2,3 Several methods to remodel the microbiome are already available:

  • Fecal microbiota transplantation from a healthy donor
  • Probiotics (live bacteria, including genetically modified species)
  • Prebiotics (e.g., dietary fibers such as inulin, and cancer-preventive polyphenols, such as flavonoids, phenolic acids, lignins) to selectively promote growth of “good” bacteria
  • Narrow-spectrum antibiotics to selectively deplete cancer-promoting bacteria
  • Medicines that block bacterial toxins or target inflammatory pathways triggered by microbes

In the future, we may learn how to use bacteria or their products to enhance therapeutic cancer vaccines, adoptive T cell therapies, and other immunotherapies, as well as traditional chemotherapy and radiation therapy.8 One critical barrier in microbiome research today is the inability to grow the majority, about 70%, of bacteria from the human gut in the lab. Researchers have been relying on genomics (e.g., next-generation sequencing) and other –omics technology to identify and study all the other gut germs. However, these approaches are not adequate to prove that specific species have beneficial or detrimental roles in cancer development.

It is too soon to offer a recipe for the ideal cancer-fighting microbiome. We will need more and larger studies to inform effective prebiotic/probiotic approaches for cancer prevention or treatment. From what we do know now, a lifestyle involving a well-balanced diet and exercise can promote a diverse microbiome associated with good health.

Read Part I of the series here

References

1. Bultman SJ: The microbiome and its potential as a cancer preventive intervention. Semin Oncol 43:97-106, 2016
2. Schwabe RF, Jobin C: The microbiome and cancer. Nat Rev Cancer 13:800-12, 2013
3. Viaud S, Daillere R, Boneca IG, et al: Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ 22:199-214, 2015
4. Shahanavaj K, Gil-Bazo I, Castiglia M, et al: Cancer and the microbiome: potential applications as new tumor biomarker. Expert Rev Anticancer Ther 15:317-30, 2015
5. Russo E, Taddei A, Ringressi MN, et al: The interplay between the microbiome and the adaptive immune response in cancer development. Therap Adv Gastroenterol 9:594-605, 2016
6. Pevsner-Fischer M, Tuganbaev T, Meijer M, et al: Role of the microbiome in non-gastrointestinal cancers. World J Clin Oncol 7:200-13, 2016
7. Poutahidis T, Kleinewietfeld M, Erdman SE: Gut microbiota and the paradox of cancer immunotherapy. Front Immunol 5:157, 2014
8. Zitvogel L, Ayyoub M, Routy B, et al: Microbiome and Anticancer Immunosurveillance. Cell 165:276-87, 2016
9. Gopalakrishnan V SC, Reuben A, et al. : Association of diversity and composition of the gut microbiome with differential responses to PD-1 based therapy in patients with metastatic melanoma. J Clin Oncol 35, 2017
10. Vetizou M, Pitt JM, Daillere R, et al: Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079-84, 2015
11. Sivan A, Corrales L, Hubert N, et al: Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084-9, 2015
12. Pitt JM, Vetizou M, Waldschmitt N, et al: Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome. Cancer Res 76:4602-7, 2016